Correlation between DIDO1 variation and MSI-status in colorectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16054-e16054
Author(s):  
Xingwei Zhang ◽  
Yonghua Cai ◽  
Yujie Hou ◽  
Huanxin Hu ◽  
Yaoxu Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Copy Number ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Copy Number Variants ◽  
Single Nucleotide Variants ◽  
Gene Variation ◽  
Immune Signature ◽  
Targeted Next Generation Sequencing ◽  
Cell Expression

e16054 Background: Several studies have displayed a sustained clinical response to immune checkpoint inhibitors with profound clinical improvement in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC). MSI-H tumors may display higher numbers of TILs, many of which can be directed against tumor-related neoantigens. We set out to examine the underline mechanism in gene level to further explain the differences between MSI-H and MSS CRC. Methods: Whole exome sequencing(WES) was performed on 68 CRC patient.MSI status of these patients were determined using a targeted next generation sequencing panel covering 100 MSI loci. TCGA database was used to analyze WES data of 364 CRC patients with different MSI states, and immune signature was used to analyze the corresponding relationship of immune cell expression in different populations. Results: Of 56 MSS patients, 58.9% (33/56) had copy number variants (CNV) in DIDO1, and 1.8 (1/56) had single nucleotide variants(SNV) in DIDO1. Of 12 MSI-H patients, 33.3% (4/12) had SNV in DIDO1 gene, None had CNV in DIDO1. TCGA database showed that of 308 MSS patients, 8% (24/308) had CNV in DIDO1 and 3% (9/308) had SNV in DIDO1. Of 56 MSI-H patient, 39% (22/56) had SNV in DIDO1 and only one patent had both SNV and CNV in DIDO1. Gene variation of DIDO1 of 68 CRC patients showed a correlation with TCGA database. Gene variation of DIDO1 in MSI-H patients are mainly SNV, and the incidence of CNV is very small (4.3% of DIDO variation).While, gene variation of DIDO1 in MSS patients are mainly CNV, followed by SNV, indicating DIDO1 CNV are highly possible occurring in MSS patients. Furthermore we analyzed the relationship between the copy number of DIDO1 and immune signature through CRC TCGA database. The results showed increase of DIDO1 copy number was negatively correlated with the abundance of NK cells (P = 0.00048), T cells (P = 8.23×10-5) and macrophages (P = 1.75×10-8). Conclusions: Our results showed that different MSI status display unique patent of DIDO1 gene variation, which may be related to different immune micro environment among MSI-H/MSS patients.

scholarly journals An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Leandro de Araújo Lima ◽  
Ana Cecília Feio-dos-Santos ◽  
Sintia Iole Belangero ◽  
Ary Gadelha ◽  
Rodrigo Affonseca Bressan ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Integrative Approach ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Hyperactivity Disorder ◽  
New Genes

Abstract Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

Basic principles of genetic disease

ESC CardioMed ◽  
2018 ◽  
pp. 669-671
Author(s):  
Eric Schulze-Bahr
Keyword(s):  
Genetic Disease ◽  
Copy Number ◽  
Copy Number Variants ◽  
Single Nucleotide Variants ◽  
Individual Genome ◽  
Base Pairs ◽  
Single Nucleotide ◽  
Basic Principles ◽  
Bona Fide ◽  
Genomic Regions

The human genome consists of approximately 3 billion (3 × 109) base pairs of DNA (around 20,000 genes), organized as 23 chromosomes (diploid parental set), and a small mitochondrial genome (37 genes, including 13 proteins; 16,589 base pairs) of maternal origin. Most human genetic variation is natural, that is, common or rare (minor allele frequency >0.1%) and does not cause disease—apart from every true disease-causing (bona fide) mutation each individual genome harbours more than 3.5 million single nucleotide variants (including >10,000 non-synonymous changes causing amino acid substitutions) and 200–300 large structural or copy number variants (insertions/deletions, up to several thousands of base-pairs) that are non-disease-causing variations and scattered throughout coding and non-coding genomic regions.

scholarly journals RefCNV: Identification of Gene-Based Copy Number Variants Using Whole Exome Sequencing

2016 ◽  
Vol 15 ◽  
pp. CIN.S36612 ◽  
Author(s):  
Lun-Ching Chang ◽  
Biswajit Das ◽  
Chih-Jian Lih ◽  
Han Si ◽  
Corinne E. Camalier ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Copy Number Variants ◽  
Estimation Methods ◽  
Single Nucleotide Variants ◽  
False Positive Error ◽  
Reference Set ◽  
Genome Wide ◽  
Whole Exome

With rapid advances in DNA sequencing technologies, whole exome sequencing (WES) has become a popular approach for detecting somatic mutations in oncology studies. The initial intent of WES was to characterize single nucleotide variants, but it was observed that the number of sequencing reads that mapped to a genomic region correlated with the DNA copy number variants (CNVs). We propose a method RefCNV that uses a reference set to estimate the distribution of the coverage for each exon. The construction of the reference set includes an evaluation of the sources of variability in the coverage distribution. We observed that the processing steps had an impact on the coverage distribution. For each exon, we compared the observed coverage with the expected normal coverage. Thresholds for determining CNVs were selected to control the false-positive error rate. RefCNV prediction correlated significantly ( r = 0.96–0.86) with CNV measured by digital polymerase chain reaction for MET (7q31), EGFR (7p12), or ERBB2 (17q12) in 13 tumor cell lines. The genome-wide CNV analysis showed a good overall correlation (Spearman's coefficient = 0.82) between RefCNV estimation and publicly available CNV data in Cancer Cell Line Encyclopedia. RefCNV also showed better performance than three other CNV estimation methods in genome-wide CNV analysis.

scholarly journals Accurate clinical detection of exon copy number variants in a targeted NGS panel using DECoN

2016 ◽  
Vol 1 ◽  
pp. 20 ◽  
Author(s):  
Anna Fowler ◽  
Shazia Mahamdallie ◽  
Elise Ruark ◽  
Sheila Seal ◽  
Emma Ramsay ◽  
...  
Keyword(s):  
False Discovery Rate ◽  
Sensitivity And Specificity ◽  
Copy Number ◽  
Clinical Laboratory ◽  
Copy Number Variants ◽  
High Sensitivity ◽  
Targeted Next Generation Sequencing ◽  
Gene Testing ◽  
False Discovery ◽  
Targeted Ngs

Background: Targeted next generation sequencing (NGS) panels are increasingly being used in clinical genomics to increase capacity, throughput and affordability of gene testing. Identifying whole exon deletions or duplications (termed exon copy number variants, ‘exon CNVs’) in exon-targeted NGS panels has proved challenging, particularly for single exon CNVs.  Methods: We developed a tool for the Detection of Exon Copy Number variants (DECoN), which is optimised for analysis of exon-targeted NGS panels in clinical settings. We evaluated DECoN performance using 96 samples with independently validated exon CNV data. We performed simulations to evaluate DECoN detection performance of single exon CNVs and evaluate performance using different coverage levels and sample numbers. Finally, we implemented DECoN in a clinical laboratory that tests BRCA1 and BRCA2 with the TruSight Cancer Panel (TSCP). We used DECoN to analyse 1,919 samples, validating exon CNV detections by multiplex ligation-dependent probe amplification (MLPA).  Results: In the evaluation set, DECoN achieved 100% sensitivity and 99% specificity for BRCA exon CNVs, including identification of 8 single exon CNVs. DECoN also identified 14/15 exon CNVs in 8 other genes. Simulations of all possible BRCA single exon CNVs gave a mean sensitivity of 98% for deletions and 95% for duplications. DECoN performance remained excellent with different levels of coverage and sample numbers; sensitivity and specificity was >98% with the typical NGS run parameters. In the clinical pipeline, DECoN automatically analyses pools of 48 samples at a time, taking 24 minutes per pool, on average. DECoN detected 24 BRCA exon CNVs, of which 23 were confirmed by MLPA, giving a false discovery rate of 4%. Specificity was 99.7%.  Conclusions: DECoN is a fast, accurate, exon CNV detection tool readily implementable in research and clinical NGS pipelines. It has high sensitivity and specificity and acceptable false discovery rate. DECoN is freely available at www.icr.ac.uk/decon.

Genetics of Schizophrenia and Bipolar Disorder

2017 ◽  
Author(s):  
Alexander Charney ◽  
Pamela Sklar
Keyword(s):  
Bipolar Disorder ◽  
Copy Number ◽  
Psychotic Disorders ◽  
Copy Number Variants ◽  
Nucleotide Polymorphisms ◽  
Common Variants ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. There is now convincing genetic evidence that indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, and there is evidence for polygenicity. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder.

PD-L1 expression on tumor cells and tumor infiltrating immune cells in Chinese colorectal cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16111-e16111
Author(s):  
Jianjun Yang ◽  
Guanghui Xu ◽  
Jiyang Zheng ◽  
Kunli Du ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Cancer Treatments ◽  
Targeted Next Generation Sequencing ◽  
Biomarker Analysis ◽  
Programmed Death 1 ◽  
Cancer Types ◽  
Colorectal Cancer Patients

e16111 Background: Nowadays, immune checkpoint inhibitors (ICIs) targeting programmed death-1/ligand-1 (PD-1/PD-L1) have been an alternative in cancer treatments. Previous biomarker analysis found that response to anti-PD1/PD-L1 was associated with PD-L1 expression on tumor cells and/or tumor infiltrating immune cells in some cancer types. Explorations of IMblaze370 study demonstrated better survival outcome in colorectal cancer (CRC) patients with positive PD-L1 expression compared with those with negative PD-L1 expression in the atezolizumab group. Our study investigated PD-L1 expression profile in Chinese CRC population. Methods: PD-L1 expression on tumor cells or tumor infiltrating immune cells in 816 CRC tumors between January 01, 2017 and December 02, 2019 in 3D Medicines database was assessed by immunohistochemistry assay (SP263 or 22C3). We defined percentage of PD-L1 expression on tumor cells as tumor proportion score (TPS) strong positive ≥50%, moderate positive ≥5% and < 50%, weak positive ≥1% and < 5%, and negative < 1%. Similarly, we defined percentage of PD-L1 expression on infiltrating immune cells as immune proportion score (IPS) strong positive ≥10%, moderate positive ≥5% and < 10%, weakly positive ≥1% and < 5%, and negative < 1%. In addition, MSI status was evaluated with targeted next-generation sequencing covering 100 MSI loci. Results: 12 (1.5%) individuals had TPS as strong positive, 63 (7.7%) as moderate positive, 95 (11.6%) as weak positive and 646 (79.2%) as negative. Meanwhile, TPS of patients were 55 (6.7%) for strong positive, 49 (6.0%) for moderate positive, 34 (4.2%) for weak positive and 678 (83.0%) for negative, respectively. 16.9% in Chinese CRC patients here were defined as positive PD-L1 expression (IPS ≥1%), which is lower than the positive proportion of CRC in IMblaze370 study (39.9% for IPS ≥1%, P < 0.0001). The PD-L1 expression on tumor cells and on tumor infiltrating immune cells showed minimal overlap. In detail, only 29 (3.6%) patients exhibited simultaneously TPS positive (≥1%) and IPS positive (≥1%). Furthermore, IPS was not associated with MSI status (P = 0.9153), while TPS showed an association with MSI-H (P < 0.0001). In detail, 45.5% of MSI-H CRC patients were TPS positive. Conclusions: Chinese CRC patients express PD-L1 with 20.8% TPS positive and 17.0% IPS positive, and TPS positive were related to MSI-H. When studying the connection between the efficacy of PD1/PD-L1 inhibitors and PD-L1 expression, TPS and IPS detection would be both considered to engage.

scholarly journals RBV: Read balance validator, a tool for prioritising copy number variations in germline conditions

2018 ◽  
Author(s):  
Whitney Whitford ◽  
Klaus Lehnert ◽  
Russell G. Snell ◽  
Jessie C. Jacobsen
Keyword(s):  
Copy Number ◽  
High Throughput Sequencing ◽  
Sequence Data ◽  
Relative Proportion ◽  
Copy Number Variants ◽  
Read Depth ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Software Packages ◽  
Bioinformatic Tool

AbstractBackgroundThe popularisation and decreased cost of genome resequencing has resulted in an increased use in molecular diagnostics. While there are a number of established and high quality bioinfomatic tools for identifying small genetic variants including single nucleotide variants and indels, currently there is no established standard for the detection of copy number variants (CNVs) from sequence data. The requirement for CNV detection from high throughput sequencing has resulted in the development of a large number of software packages. These tools typically utilise the sequence data characteristics: read depth, split reads, read pairs, and assembly-based techniques. However the additional source of information from read balance, defined as relative proportion of reads of each allele at each position, has been underutilised in the existing applications.ResultsWe present Read Balance Validator (RBV), a bioinformatic tool which uses read balance for prioritisation and validation of putative CNVs. The software simultaneously interrogates nominated regions for the presence of deletions or multiplications, and can differentiate larger CNVs from diploid regions. Additionally, the utility of RBV to test for inheritance of CNVs is demonstrated in this report.ConclusionsRBV is a CNV validation and prioritisation bioinformatic tool for both genome and exome sequencing available as a python package from https://github.com/whitneywhitford/RBV

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